224
16.1 Recombinant sFlt-1 chimeric proteins -Wet AMD
Intravitreal
Inhibition of VEGF by intravitreal injections of recom-
binant sFlt-1 chimeric proteins and antisense oligode-
oxynucleotides have been shown to prevent retinal neo-
vascularization in mouse models
(74)
.
16.2 AdsFlt-1 - Wet AMD
Intravitreal
Intraocular injection of AdsFlt-1 suppressed retinal and
choroidal neovascularization
(72-73,75)
. Periocular injection
of AdsFlt-1 resulted in transduction of episcleral cells,
penetration of the sclera and high levels of AdsFlt-1 in
the choroid, which markedly suppressed CNV
(70)
. Long-
term suppression of CNV was achieved with intraocular
injection of AAVsFlt-1 in mice and monkeys
(75)
.
17. Others
17.1 Ciliary neurotrophic factor - Dry AMD
Implant
Ciliary neurotrophic factor (CNTF) is being investi-
gated as a treatment for dry AMD because it has a potent
neuroprotective action; it has been shown to inhibit
photoreceptor apoptosis in an animal model of retinal
degeneration. CNTF has been shown to slow photorecep-
tor degeneration in animal models of retinal degenerations
and thus may be effective in protecting photoreceptors in
AMD
(76)
. A phase II trial utilizes an encapsulated cell tech-
nology (ECT) to deliver CNTF to the retina. The implant
is a small capsule that contains human retinal pigment
epithelium cells. These cells have been given the ability
to make CNTF and release it through the capsule mem-
brane into the surrounding fluid. In this study, two dif-
ferent CNTF dose levels will be used: a high dose and a
low dose, as well as a sham surgery (or placebo) group
(77)
.
The cells can survive for approximately 18 months fol-
lowing implantation into the vitreous cavity with a sin-
gle scleral suture
(78)
. The trial, sponsored by Neurotech
Pharmaceuticals USA (Lincoln, RI), is ongoing and not
recruiting.
17.2 Rheopheresis - Dry AMD
Rheopheresis is still an unproven therapy for dry macu-
lar degeneration. Rheopheresis is a form of therapeutic
plasmapheresis designed to remove species circulating in
the blood that are larger than 25 nm (about 500 kilodal-
tons) using a doublestaged membrane filtration system.
The intended targets include immune complexes, immu-
noglobulin M, beta 2-macroglobulin, fibrinogen, von
Willebrand factor, low density lipoprotein cholesterol,
and others
(79)
.
“This procedure has been proposed as a possible treat-
ment to prevent the progression of dry AMD by improv-
ing the retinal and choroidal microcirculation. The
largest study performed to assess the effectiveness of rhe-
opheresis in dry AMD is the Multicenter Investigation
of Rheopheresis for Age-related macular degeneration
(MIRA-1) trial. Study patients had at least 10 soft drusen
within 2 disc diameters from the foveal center and/or
GA. Interpretation of the results from the MIRA-1
trial has been controversial. The sole outcome measure
was LogMAR VA. At 1 year, the treated group had a
LogMAR VA of 0.02 ±0.213, and the placebo patients
had a VA of 0.02 ±0.20 (P=.977). This may have implied
that the treatment was not effective in improving VA.
However, a post hoc analysis showed that a large propor-
tion of the subjects (37% of treated and 29% of placebo)
were mistakenly included in the trial and that a number
of the subjects did not receive the required number of
rheopheresis treatments. When reanalyzed, the treat-
ment arm of this “modified per protocol” group of sub-
jects did have a statistically significant improvement in
visual acuity (treated improved 0.08 ±0.166, placebo
decreased 0.01 ±0.164, P=.001). Furthermore, a larger
proportion of treated subjects experienced an adverse
event requiring intervention (24.0%) compared to those
receiving placebo (5.8%)
(80)
. The Occulogix (Waltham,
MA) phase II study was suspended.“
(82-83)
17.3 Improvements in ophthalmic drug delivery
“Ophthalmic drugs have traditionally been adminis-
tered topically, which in general provides therapeutic
levels to the anterior chamber of the eye but not to the
posterior segment. Therefore, topical administration of
drugs has been largely infeasible for posterior segment
diseases such as AMD and diabetic macular oedema. In
contrast, intravitreous injection provides direct delivery
to the posterior segment and allows therapeutic levels
to be attained. However, this route of administration
can require repeated injections for chronic disorders and
is associated with a small risk of complications. Several
alternative strategies for drug delivery have therefore been
developed, such as implantable devices that deliver small,
